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The Latest Research Items

Selective Receptors

A new small molecule receptor, A2N, has been identified that binds specifically to trimethyllysine, Kme3, with sub-micromolar affinity. This receptor, as published in Organic & Biomolecular Chemistry was discovered by Nicholas Pinkin and Marcey Waters in the Waters Group, through the iterative redesign of a monomer known to incorporate through dynamic combinatorial chemistry, DCC, into a previously reported receptor for Kme3, A2B. In place of monomer B, the newly designed monomer N introduces an additional cation–Π interaction into the binding pocket, resulting in more favorable binding to Kme3 amounting to a ten-fold improvement in affinity and a five-fold improvement in selectivity over Kme2.

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This receptor exhibits the tightest affinity and greatest selectivity for Kme3-containing peptides reported to date. Comparative studies of A2B and A2N provide mechanistic insight into the driving force for both the higher affinity and higher selectivity of A2N, indicating that the binding of Kme3 to A2N is both enthalpically and entropically more favorable. This work demonstrates the ability of iterative redesign coupled with DCC to develop novel selective receptors with the necessary affinity and selectivity required for biological applications.

 

Hierarchically-Structured NiO Nanoplatelets

A p-type metal oxide with high surface area and good charge carrier mobility is of paramount importance for development of tandem solar fuel and dye-sensitized solar cell, DSSC, devices. Published in the Journal of Physical Chemistry, researchers in the Cahoon Group report the synthesis, hierarchical morphology, electrical properties, and DSSC performance of mesoscale p-type NiO platelets.

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This material, which exhibits lateral dimensions of 100 nm but thicknesses less than 10 nm, can be controllably functionalized with a high-density array of vertical pores 4–6, 5–9, or 7–23 nm in diameter depending on exact synthetic conditions. Thin films of this porous but still quasi-two-dimensional material retain a high surface area and exhibit electrical mobilities more than 10-fold higher than comparable films of spherical particles with similar doping levels. These advantages lead to a modest, 20–30% improvement in the performance of DSSC devices under simulated 1-sun illumination. The capability to rationally control morphology provides a route for continued development of NiO as a high-efficiency material for tandem solar energy devices.

 

Shapeshifting

Biological systems have the ability to program reversible shape changes in response to cues from their environment. While a variety of adaptive and stimuli-responsive materials like hydrogels, liquid crystalline elastomers, and shape memory materials have been developed, mimicking programmable behavior in a reversible way remains elusive.

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Work published in Macromolecules by the Sheiko and Ashby groups, in collaboration with the University of Connecticut, Brookhaven and Oak Ridge National Labs, has shown that semi-crystalline elastomers may undergo reversible switching between well-defined shapes without applying any external forces. This behavior stems from the correlated interplay between a crystalline scaffold and a network of chemical crosslinks, each capable of encoding a distinct shape. The universal mechanism of reversible shapeshifting affords interesting opportunities for minimally invasive surgery, shape programmable biomedical implants, surgical sealants, and hands-free packaging.

 

Nitric Oxide-Releasing Glucose Biosensors

In vivo glucose biosensors have the potential to greatly improve the way diabetics manage their disease. Unfortunately, such devices do not function as intended, that is, reliably, after implantation due to inflammation and encapsulation due to the "foreign body response.” The Schoenfisch Group has for the last decade researched the benefits of materials that release nitric oxide, NO, to mitigate the foreign body response. In an article published in Analytical Chemistry, they describe the analytical performance benefits of a NO-releasing glucose biosensor percutaneously implanted in a swine model.

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Needle-type glucose biosensors were modified with NO-releasing polyurethane coatings designed to release similar total amounts of NO for either rapid or slower durations, and remain functional as outer glucose sensor membranes. Relative to controls, NO-releasing sensors were characterized with improved numerical accuracy on days one and three.

The clinical accuracy and sensitivity of rapid NO-releasing sensors were superior to control and slower NO-releasing sensors at both one and three days after implantation. In contrast, the slower/extended NO-releasing sensors were characterized by shorter sensor lag times in response to intravenous glucose tolerance tests versus burst NO-releasing and control sensors. Collectively, these results highlight the great potential for NO release to enhance the analytical utility of in vivo glucose biosensors. Initial results also suggest that this analytical performance benefit is dependent on the NO-release duration.

 

Cerebral Blood Flow

Neurovascular coupling is understood to be the underlying mechanism of functional hyperemia, but the actions of the neurotransmitters involved are not well characterized. In an article published in the Journal of Cerebral Blood Flow & Metabolism, researchers in the Wightman Group investigate the local role of the neurotransmitter norepinephrine in the ventral bed nucleus of the stria terminalis, vBNST, of an anesthetized rat by measuring O2, which is delivered during functional hyperemia. Extracellular changes in norepinephrine and O2 were simultaneously monitored using fast-scan cyclic voltammetry. Introduction of norepinephrine by electrical stimulation of the ventral noradrenergic bundle or by iontophoretic ejection induced an initial increase in O2 levels followed by a brief dip below baseline.

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Supporting the role of a hyperemic response, the O2 increases were absent in a brain slice containing the vBNST. Administration of selective pharmacological agents demonstrated that both phases of this response involve β-adrenoceptor activation, where the delayed decrease in O2 is sensitive to both α- and β-receptor subtypes. Selective lesioning of the locus coeruleus with the neurotoxin DSP-4 confirmed that these responses are caused by the noradrenergic cells originating in the nucleus of the solitary tract and A1 cell groups. Overall, these results support that non-coerulean norepinephrine release can mediate activity-induced O2 influx in a deep brain region.

 

Osmolytes and Protein Crowding

In an article that not only made the cover of Protein Science, but also is a highlighted article in that issue and accompanied by an online video, then graduate student Mohona Sarkar in the Pielak Group, now a postdoc at Notre Dame University, and Professor Gary Pielak, suggest the reason why small molecules, called osmolytes, are used to overcome the effects of environmental stress.

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Osmolytes are ubiquitous in biology. Given that dehydration stress adds to the crowded nature of the cytoplasm, the team speculated that cells might use osmolytes to overcome the destabilization caused by the increased attractive interactions that accompany desiccation. They used NMR-detected amide proton exchange experiments to measure the stability of the test protein chymotrypsin inhibitor 2 under physiologically relevant crowded conditions in the presence and absence of the osmolyte glycine betaine. The osmolyte overcame the destabilizing effect of the cytosol, a result that provides a physiologically relevant explanation for the accumulation of osmolytes by dehydration-stressed cells.

 

Massively Parallel Clonogenic Screening

Wnt/β-catenin signaling is of significant interest due to the roles it plays in regulating development, tissue regeneration and disease. Transcriptional reporters have been widely employed to study Wnt/β-catenin signal transduction in live cells and whole organisms and have been applied to understanding embryonic development, exploring oncogenesis and developing therapeutics. Polyclonal heterogeneity in reporter cell lines has historically been seen as a challenge to be overcome in the development of novel cell lines and reporter-based assays, and monoclonal reporter cell lines are commonly employed to reduce this variability.

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Published in Integrative Biology, researchers in the Allbritton Group describe how A375 cell lines infected with a reporter for Wnt/β-catenin signaling were screened over short (<6) and long (>25) generational timescales. To characterize phenotypic divergence over these time-scales, a microfabricated cell array-based screen was developed enabling characterization of 1119 clonal colonies in parallel. This screen revealed phenotypic divergence after <6 generations at a similar scale to that observed in monoclonal cell lines cultured for >25 generations. Not only were reporter dynamics observed to diverge widely, but monoclonal cell lines were observed with seemingly opposite signaling phenotypes. Additionally, these observations revealed a generational-dependent trend in Wnt signaling in A375 cells that provides insight into the pathway's mechanisms of positive feedback and self-inhibition.

 

New Avenues in Solar Fuel Production

Chemists have long sought new ways to create energy-rich fuels - ideally via reactions powered by a renewable resource such as the sun. But scientists still have a lot to learn about solar-powered reactions, and a new study by Thomas Eisenhart and Jillian Dempsey sheds light on how they occur. The proton-coupled electron transfer reaction, PCET, is a key light-driven step in the conversion of small molecules into energy-rich fuels. Although prior research has provided a basic understanding of PCET reactions between molecules in their ground states, much less is known about the reactions between electronically excited molecules.

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In the article, which made the cover of JACS, and was also featured in JACS Spotlights, the team reports results from a mechanistic study of excited-state PCET reactions between two small molecules, acridine orange and tri-tert-butylphenol. The step-by-step process by which the reaction occurs has not been determined previously, but since each of the reaction components has a unique spectroscopic signature, the researchers can monitor each step with transient absorption spectroscopy. The results help explain the intimate coupling of light absorption with both proton and electron transfer, which the authors say will help pave the way for new avenues in solar fuel production.

Christine Herman, Ph.D., JACS

 

SHAPE-MaP RNA Structure Analysis

Many central biological processes are mediated by complex RNA structures, but the higher-order interactions for most RNAs are unknown, which makes it difficult to understand how RNA structure governs function. As published in Nature Methods, a team of students in the Weeks lab have invented a new approach -- selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) -- that makes possible de novo and large-scale identification of RNA functional motifs.

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SHAPE-MaP melds chemistry invented in the Weeks lab with readout by massively parallel sequencing to make it possible to detect structure-selective chemical reactions in RNA on genome-wide scales. SHAPE-MaP represents a "no compromises" approach for interrogating the structure of RNA, enables analysis of low-abundance RNAs, and is ultimately poised to democratize RNA-structure analysis.

 

Waveguide Scattering Microscopy

Dark-field microscopy, DFM, is widely used to optically image and spectroscopically analyze nanoscale objects. In a typical DFM configuration, a sample is illuminated at oblique angles and an objective lens collects light scattered by the sample at a range of lower angles. As demonstrated in an article published as the cover of ACS Photonics, researchers in the Cahoon Group have developed waveguide scattering microscopy, WSM, as an alternative technique to image and analyze photonic nanostructures. WSM uses an incoherent white-light source coupled to a dielectric slab waveguide to generate an evanescent field that illuminates objects located within several hundred nanometers of the waveguide surface.

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Using standard microscope slides or coverslips as the waveguide, the group demonstrate high-contrast dark-field imaging of nanophotonic and plasmonic structures such as Si nanowires, Au nanorods, and Ag nanoholes. Scattering spectra collected in the WSM configuration show excellent signal-to-noise with minimal background signal compared to conventional DFM. In addition, the polarization of the incident field is controlled by the direction of the propagating wave, providing a straightforward route to excite specific optical modes in anisotropic nanostructures by selecting the appropriate input wavevector. Considering the facile integration of WSM with standard microscopy equipment, the Cahoon Group scientists anticipate it will become a versatile tool for characterizing photonic nanostructures.

 

Polyelectrolyte Microgels

Lowering the modulus of hydrogel particles could enable them to bypass in vivo physical barriers that would otherwise filter particles with similar size but higher modulus. Incorporation of electrolyte moieties into the polymer network of hydrogel particles to increase the swelling ratio is a straightforward and quite efficient way to decrease the modulus. In addition, charged groups in hydrogel particles can also help secure cargoes. However, the distribution of charged groups on the surface of a particle can accelerate the clearance of particles.

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Published in JACS, researchers in the DeSimone Group have developed a method to synthesize highly swollen microgels of precise size with near-neutral surface charge while retaining interior charged groups. A strategy was employed to enable a particle to be highly cross-linked with very small mesh size, and subsequently PEGylated to quench the exterior amines only without affecting the internal amines. Acidic degradation of the cross-linker allows for swelling of the particles to microgels with a desired size and deformability. The microgels fabricated demonstrated extended circulation in vivo compared to their counterparts with a charged surface, and could potentially be utilized in in vivo applications including as oxygen carriers or nucleic acid scavengers.

 

Layer-by-Layer Chromophore–Catalyst

As described in Chemical Science, members of the Dempsey Group, in collaboration with the Meyer Group, used a layer-by-layer procedure to prepare chromophore–catalyst assemblies consisting of phosphonate-derivatized porphyrin chromophores and a phosphonate-derivatized ruthenium water oxidation catalyst on the surfaces of tin oxide and titanium dioxide mesoporous, nanoparticle films. In the procedure, initial surface binding of the phosphonate-derivatized porphyrin is followed in sequence by reaction with a zirconium salt and then with the phosphonate-derivatized water oxidation catalyst.

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Fluorescence from both the free base and zinc porphyrin derivatives on tin oxide is quenched; substantial emission quenching of the zinc porphyrin occurs on titanium dioxide. Transient absorption difference spectra provide direct evidence for appearance of the porphyrin radical cation on tin oxide via excited-state electron injection. For the chromophore–catalyst assembly on tin oxide, transient absorption difference spectra demonstrate rapid intra-assembly electron transfer oxidation of the catalyst following excitation and injection by the porphyrin chromophore.

 

Hydrohalogenation of Styrenyl Alkenes

The direct anti-Markovnikov addition of strong Bronsted acids to alkenes remains an unsolved problem in synthetic chemistry. Published in Nature Chemistry, researchers in the Nicewicz Group report an efficient organic photoredox catalyst system for the addition of HCl, HF and also phosphoric and sulfonic acids to alkenes, with complete regioselectivity. These transformations were developed using a photoredox catalyst in conjunction with a redox-active hydrogen atom donor.

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The nucleophile counterion plays a critical role by ensuring high reactivity, with 2,6-lutidinium salts typically furnishing the best results. The nature of the redox-active hydrogen atom donor is also consequential, with 4-methoxythiophenol providing the best reactivity when 2,6-lutidinium salts are used. A novel acridinium sensitizer provides enhanced reactivity within several of the more challenging reaction manifolds. Thew work published by the Nicewicz team demonstrates how nucleophilic addition reactions mediated by photoredox catalysis can change the way electrophilic and homofugal precursors are constructed.

 

Ultrafast Electron Transfer

Kinetic models based on Fermi's Golden Rule are commonly employed to understand photoinduced electron transfer dynamics at molecule-semiconductor interfaces. Implicit in such second-order perturbative descriptions is the assumption that nuclear relaxation of the photoexcited electron donor is fast compared to electron injection into the semiconductor. This approximation breaks down in systems where electron transfer transitions occur on 100-fs time scale. In an article published in the Journal of Chemical Physics, researchers in the Moran and Kanai Groups present a fourth-order perturbative model that captures the interplay between time-coincident electron transfer and nuclear relaxation processes initiated by light absorption.

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The model consists of a fairly small number of parameters, which can be derived from standard spectroscopic measurements, for example linear absorbance or fluorescence, and/or first-principles electronic structure calculations. Insights provided by the model are illustrated for a two-level donor molecule coupled to both (i) a single acceptor level and (ii) a density of states, DOS, calculated for TiO2 using a first-principles electronic structure theory. These numerical calculations show that second-order kinetic theories fail to capture basic physical effects when the DOS exhibits narrow maxima near the energy of the molecular excited state. Overall, the team concludes that the present fourth-order rate formula constitutes a rigorous and intuitive framework for understanding photoinduced electron transfer dynamics that occur on the 100-fs time scale.